Background/objective: Increased physical activity (PA) and decreased sedentary behaviors (SBs) may have beneficial effects on cardio-metabolic risk in adolescents. The aim of this study was to examine the associations between independent/combined effects of PA and SB with individual/clustered cardio-metabolic risk factors. Methods: A sample of 769 adolescents (12.5-17.5 years) from the HELENA cross-sectional study (Healthy Lifestyle in Europe by Nutrition in Adolescence) and with valid data on metabolic risk factors were included. Results: Concerning moderate-to-vigorous-PA (MVPA) and vigorous-PA (VPA), measured with accelerometers, girls tended to domoreMVPA (36%) and VPA (114%) than boys. Unadjusted analyses show a positive association between “PA >= 60 min/d; SB >= 2 h” and the ratio TC/HDL-c (beta = 0.27; 95% CI 0.01 to 0.52; p < 0.05), and a negative association between "MVPA = 60 min/d; SB < 2 h" with the Sigma 4Skinfolds (beta = -0.32; 95% CI - 0.61 to -0.02; p < 0.05). Moreover, "SB >= 2 h/d” was associated with increased cardio-metabolic risk (PR 1.59; 95% CI 1.05 to 2.39; p < 0.05), while "PA >= 60 min/d; SB < 2 h" had a protective effect against cardio-metabolic risk (PR 0.48; 95% CI 0.25 to 0.91; p < 0.05). After adjustment for potential confounders, a positive association between SB and Sigma 4Skinfolds was shown (beta = 0.28; 95% CI 0.04 to 0.53; p < 0.05). Furthermore, VO(2)max (mL/kg/min) tends to increase in those participants who do higher VPA and less SB (p = 0.042), and there was a protective effect of "VPA >= 30 min/d; SB < 2 h" against cardio-metabolic risk (PR 0.24; 95% CI 0.07 to 0.85; p < 0.05). Conclusion: The current study suggests that adolescents should be encouraged to decrease sedentary lifestyle and increase physical activity, especially vigorous physical activity, in order to reduce cardio-metabolic risk. (C) 2015 Elsevier Ireland Ltd. All rights reserved.